The inactivation of the human DNA repair protein O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) by O.sup.6 -benzylguanine leads to a dramatic enhancement in the cytotoxic response of human tumor cells and tumor xenografts to chemotherapeutic drugs whose mechanism of action involves modification of DNA guanine residues at the O.sup.6 -position (Dolan et al., Proc. Natl. Acad. Sci. U.S.A., 87, 5368-5372 (1990); Dolan et al., Cancer Res., 51, 3367-3372 (1991); Dolan et al., Cancer Commun., 2, 371-377 (1990); Mitchell et al., Cancer Res., 52, 1171-1175 (1992); Friedman et al., J. Natl. Cancer Inst., 84, 1926-1931 (1992); Felker et al., Cancer Chem. Pharmacol., 32, 471-476 (1993); Dolan et al., Cancer Chem. Pharmacol., 32, 221-225(1993); Dolan et al., Biochem. Pharmacol., 46, 285-290 (1993)). The AGT inactivating activity of a large number of O.sup.6 -benzylguanine analogs have been compared with the aim of obtaining information about the types of substituent groups and the sites at which they could be attached to O.sup.6 -benzylguanine without significantly lowering its AGT-inactivating activity (Moschel et al., J. Med. Chem., 35, 4486-4491 (1992); Chae et al., J. Med. Chem., 37, 342-347 (1994)). While these studies led to the production of a variety of analogs that were as potent or somewhat less potent than O.sup.6 -benzylguanine, none of the analogs were better than O.sup.6 -benzylguanine.
Thus, there remains a need for additional compounds which are capable of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine. The present invention provides such compounds and associated pharmaceutical compositions and treatment methods. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.